Since the beginning of this project we have screened over 1300 subjects for this study. We have enrolled approximately 180 youth with bipolar disorder (BD), 240 subjects at risk for BD because they have a parent or sibling with the illness, and 100 adults with BD. This year, approximately 20 new subjects were enrolled. This year we continued our work designed to identify the brain mechanisms underlying BD in children; compare brain function in youth and adults with BD in order to begin to understand how the illness develops over time; and compare brain function in youth at familial risk for BD to those with BD and those at low risk, in order to facilitate the eventual development of preventive interventions. In terms of our work on the brain mechanisms mediating BD, much of that work consists of, not only comparing youth with BD to healthy youth, but also comparing youth with BD to those with severe, chronic irritability (the so-called severe mood dysregulation, or SMD, population, see MH002786-07). It is important to compare youth with BD and those with SMD because the latter frequently receive the diagnosis of BD in the community, despite not having a history of manic episodes. In previous work, we demonstrated that both youth with BD and those with SMD have deficits in labeling face emotion. Studies in other clinical populations (e.g., children with autism) demonstrate that such deficits can be associated with failure to look at people's eyes when processing the emotion on a face. To test whether such a deficit occurs, we conducted a study in which subjects eye movements were recorded while they attempted to label face emotion. Youth with BD, compared to healthy youth, made more errors in labeling the face emotion, and spent less time looking at eyes and more time looking at the nose. Amount of time looking at the nose was inversely related to accuracy labeling face emotion. This work both further implicates amygdala deficits in BD (since there are associations between amygdala damage and failure to look at eyes) and has potential treatment implications (would teaching children to focus on eyes improve their ability to label face emotion?). This work is submitted for publication. We are now examining eye tracking patterns in adults with BD, as well as in youth at familial risk for the illness. With regard to amygdala function, in one study accepted for publication and another that was recently submitted, we found that youth with BD, as well as those with SMD, have deficits in amygdala function while viewing emotional faces. In the first study, both patient populations failed to modulate amygdala activity appropriately while viewing angry faces. Specifically, healthy subjects showed increased amygdala activity as the amount of anger on a face increased, while neither of the patient samples did so. This failure to modulate amygdala activity in response to subtle changes in face emotion might be associated with the deficit in face emotion labeling that patients exhibit. In the second study, both patient populations showed amygdala hyperactivation in response to angry and fearful faces, again showing difficulty modulating amygdala activity appropriately in response to face emotions. While the SMD and BD populations did not differ in amygdala activity, they did differ in activity in other brain regions. Specifically, youths with BD showed decreased activation (compared to both SMD and healthy subjects) in anterior cingulate (ACC), insula, and parietal regions while processing angry faces. Finally, in a large sample of adults and youth with bipolar disorder, we attempted to dissociate the impact of face emotion and attentional state (e.g., rating emotion on the face, rating ones own emotion) on neural activity. There was amygdala hyperactivation in BD to angry, fearful, and neutral faces during both explicit processing (hostility ratings) and passive viewing. In the frontal cortex and striatum, however, the direction of dysfunction varied by attentional state: BD demonstrated hyperactivation of the ACC, dorsolateral prefrontal cortex (PFC), and putamen during unconstrained processing of angry or neutral faces, but ACC, ventrolateral PFC, and putamen hypoactivation during constrained processing (implicit or explicit) of angry, neutral, or happy emotions. These results suggest that amgydala hyperactivation in BD is present in response to negative-valence faces across a number of different tasks, but that abnormal activity in other brain regions is more dependent on specific task demands. In addition to this work on brain function, we also have a paper in press that examines brain structure in youth with BD. Importantly, this work examines brain structure longitudinally as well as cross-sectionally. Cross-sectionally, the groups differed in gray matter (GM) volume in presupplementary motor area (pre-SMA), dorsolateral PFC, insula, and globus pallidus. The cortical differences were driven mainly by increased GM volume in healthy subjects compared with BD and SMD. In globus pallidus, there was increased GM in BD compared with healthy subjects and SMD. When scanning was repeated over two years, subjects with BD showed an abnormal increase in volume in two clusters in the superior/inferior parietal lobule and in the precuneus. Abnormal developmental trajectories in lateral parietal cortex and precuneus are present in, and unique to, BD. Comparing youth and adults with BD, we have now demonstrated that adults with BD, like youth with the illness, have deficits in face memory. In both groups, we were able to demonstrate that this deficit is associated with hypoactivation in the fusiform gyrus, a region that plays a central role in the processing of emotional faces. Our work in at risk children continues, in that we are accruing fMRI data on a large sample of children at risk for BD. We have also continued to establish the relationships that would allow us to assess Amish children at risk for BD, and that work is progressing. In addition, we have demonstrated previously behaviorally that children at risk for BD have attentional lapses, as evidenced by increased variability in their response time on motor tasks. We have now devised a sophisticated neuroimaging paradigm to allow us to examine the neural correlates of this deficit, and we have begun to implement it in both children with BD and those at risk for the disorder by virtue of having an affected first-degree relative.